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Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors
in Non-Small Cell Lung Cancer
Kuiper, J.L.
2016
document version
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citation for published version (APA)
Kuiper, J. L. (2016). Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer.
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ABSTRACT
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It is believed that cancer arises from a single common ancestor cancer cell (1). The development of this one cell to metastatic cancer is a multifactorial process, influenced by clonal selection, according to historical evolution theories. Genetic instability and epigenetic events lead to the survival of the ‘fittest’ clones and at time of clinical presentation, tumours consist of multiple molecularly distinct tumour cell populations (2). The populations with the highest proliferation rate predominate in the tumour lesions. Consequently a tissue biopsy or cytological sample for diagnostic purposes will most likely be procured from this dominating part. Subsequently, this small sample from the dominating part will be considered to be representative for the whole tumour, primary and metastatic lesions. Even till very recently the initially obtained tissue was the only sample used for decision-making throughout the whole treatment period, even far beyond first line treatment, despite the well-known and well-described phenomenon of tumour heterogeneity (3, 4). Physiological and iatrogenic events, for instance anti-tumour therapy, may modify the clonal selection process. With modern therapies that are aimed at a specific target, nowadays described as ‘targeted therapy’, this effect is even more pronounced than with traditional chemotherapy.
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mutation have higher TKI binding affinity compared to tumours with wild-type EGFR (7). Therefore, increased [11C]erlotinib uptake is indicative of (parts of the) tumour lesions that
are sensitive to TKI-treatment (8).
A 46-year-old Asian woman was diagnosed with EGFR+ (exon 19 deletion) NSCLC (T3N3M1b), in the right upper lobe (RUL). Prior to treatment with erlotinib, an [11C]erlotinib PET scan
was performed (8) (Figure 1A). The overall tumour [11C]erlotinib uptake was quantified by
pharmacokinetic analysis in a 2-tissue reversible model using volume of distribution (VT) as a measure of uptake, as previously described (8). A tumour VT of 1.33 ± 0.03 and 1.90 ± 0.04 was measured during test and retest, respectively. Homogeneously increased uptake of [11C]
erlotinib was observed both in the tumour and in enlarged mediastinal lymph nodes. After start of erlotinib in standard dosage the patient obtained a partial response that lasted for 18 months. Then, there was progression in the primary tumour and a biopsy of this lesion showed the known EGFR exon 19 deletion, and a T790M mutation (molecular analysis performed by EGFR/KRAS high resolution melting (HRM) pre-screen with sequential analysis confirmation (9)). The [11C]erlotinib scan was repeated after discontinuation of erlotinib for approximately
1 week (Figure 1B). This scan showed a VT value of 1.09 ± 0.02, indicating a decrease of 18% and 43%, as compared to test and retest, respectively. Also, by visual assessment, the intratumour [11C]erlotinib uptake pattern had become heterogeneous, suggesting that also
tumour affinity to TKI had become more heterogeneous. In retrospect the area where the new biopsy was taken, the dorsal part of the tumour, had little uptake of [11C]erlotinib.
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(A) Prior to treatment
(B) After treatment with erlotinib
Figure 1: Positron emission tomography scan showing [11C]erlotinib uptake in the tumour
(A) Prior to treatment
